Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, International Joint Laboratory of Ocular Diseases, School of Pharmacy, Tianjin Medical University, Tianjin 300070, China.
Department of Immuno-oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, China.
J Control Release. 2024 Apr;368:52-65. doi: 10.1016/j.jconrel.2024.02.025. Epub 2024 Feb 21.
FOLFOX regimen, composed of folinic acid, 5-fluorouracil (5-FU) and oxaliplatin (OXP), has been used as clinical standard therapeutic regimen in treatments of colorectal cancer (CRC) and esophageal squamous cell carcinoma (ESCC). To further improve its therapeutic outcomes, FOLFOX was combined with anti-PD-1 antibody to form an advanced chemo-immune combination strategy, which has been proven more efficient in controlling cancer progression and prolonging patients' survival in various clinical trials. However, bad tumor accumulation, relative high toxicity, numerous treatment cycles with high fees and low compliance as well as drug resistance seriously limit the prognosis of FOLFOX regimen. The "all-in-one" formulations, which could precisely delivery multidrug regimen into tumor sites and cells, showed a promising application prospect for targeted drug delivery as well as reducing side effects. However, the design and preparation of the "all-in-one" formulation with high drug encapsulation efficiencies for all drugs was still challenging. Herein, a lipid core-shell nanoparticle codelivery platform was designed for simultaneous encapsulation of variant FOLFOX composed of miriplatin (MiPt), 5-Fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP), calcium folinate (CF) and PD-L1 siRNA (siPD-L1) with high efficiencies, and their synergistic anti-tumor mechanisms were studied, respectively. MiPt, a precursor of OXP, was validated capable of inducing efficient immunogenic cell death (ICD) in this work. Additionally, ICD-mediated release of damage associated molecular patterns functionalized synergistically with PD-L1 silence by siPD-L1 to overcome chemoresistance, reverse suppressive tumor microenvironment and recruit more CD8 T cells. FdUMP, as the intracellular active form of 5-FU, could induce large amounts of reactive oxygen species to enhance the ICD. CF worked as the sensitizer of FdUMP. The enhanced long-term anti-tumor effect of the prepared "all-in-one" formulation compared to free drug regimen and other controls, was verified in heterotopic CRC mice models and ESCC mice models, providing new thoughts for researchers and showing a promising prospect of translation into clinical applications.
奥沙利铂、亚叶酸钙和氟尿嘧啶（5-FU）组成的 FOLFOX 方案已被广泛应用于结直肠癌（CRC）和食管鳞癌（ESCC）的临床标准治疗方案。为了进一步提高其治疗效果，将 FOLFOX 与抗 PD-1 抗体联合形成了一种先进的化疗免疫联合策略，在多项临床试验中已证明该策略在控制癌症进展和延长患者生存方面更有效。然而，较差的肿瘤积累、相对较高的毒性、多个治疗周期、高费用和低顺应性以及耐药性严重限制了 FOLFOX 方案的预后。“一体化”制剂能够精确地将多药制剂递送到肿瘤部位和细胞中，为靶向药物输送和降低副作用提供了有前途的应用前景。然而，设计和制备具有高药物包封效率的“一体化”制剂以同时包封各种药物仍然具有挑战性。在此，设计了一种脂质核壳纳米粒子共递药平台，用于高效地同时包封由米铂（MiPt）、5-氟-2'-脱氧尿苷 5'-单磷酸（FdUMP）、亚叶酸钙（CF）和 PD-L1 siRNA（siPD-L1）组成的变体 FOLFOX，并分别研究了它们的协同抗肿瘤机制。MiPt 作为 OXP 的前体，在本工作中被验证能够诱导有效的免疫原性细胞死亡（ICD）。此外，ICD 介导的损伤相关分子模式的释放与 siPD-L1 沉默协同作用，克服化疗耐药性，逆转抑制性肿瘤微环境并招募更多 CD8 T 细胞。FdUMP 作为 5-FU 的细胞内活性形式，能够诱导大量活性氧来增强 ICD。CF 作为 FdUMP 的敏化剂。与游离药物方案和其他对照组相比，在异质 CRC 小鼠模型和 ESCC 小鼠模型中验证了所制备的“一体化”制剂的增强的长期抗肿瘤效果，为研究人员提供了新的思路，并展示了转化为临床应用的广阔前景。
